Interference of TGFb with the activation state of liver macrophages and consequences for liver injury and regeneration

Changes that macrophage populations of the liver undergoes in terms of composition and activation state in the context of liver regeneration are incompletely understood. This and the question of what influence cell populations that significantly influence the microenvironment of the liver, such as hepatocytes, have on the activation state of liver macrophages and which mediators are relevant in this context was the aim of the present investigations.

Analysis of the changes in the macrophage populations of the liver in vivo after partial hepatectomy (PHx) by flow cytometry and single cell sequencing. Investigation of intercellular communication by proteomic/secretomic/transcriptomic analyses using a coculture model.

In this study, a CCR2-dependently recruited macrophage subpopulation, characterized by high expression of CD11b and CD14 was identified that is rapidly recruited into the liver after PHx, reaching its maximum just one day after PHx. Under homeostatic conditions, this F4/80+/CD11bhigh/CD14high macrophage population exhibits a particular polarization, which is temporarily lost after PHx, but reappears during the late phase of the regeneration process. Thereby, the availability of active TGFb plays a role in the intercellular communication network by which hepatocytes can influence polarization of this macrophage population. Lack of the TGFbRII in macrophages has particular influence on function and gene expression of F4/80+/CD11bhigh/CD14high macrophages and results in prolongation of the proliferation phase of hepatocytes and accelerated regeneration after PHx.

TGFbRII mediated signaling influences in particular the activation state of macrophages CCR2 dependently recruited in the liver and thereby limits hepatocyte proliferation and aggravates injury caused by the surgical intervention.

Publication History

Article published online:
26 January 2022